Recent Genome Wide Association Studies have identified several microglia-expressed genes as conferring increased risk of developing Alzheimer's disease, while activated microglia are a prominent feature of the AD brain. It is critical that we determine how microglia confer risk of development of AD in order to devise appropriate therapeutics. We have developed a method to eliminate all microglia from the adult brain, even for the lifetime of the animal. This elimination allows us to fully study how microglia influence the pathogenesis of AD, and determine their roles in the disease. Our preliminary data has demonstrated that we can completely eliminate microglia from AD mice prior to any pathology development, and we can keep the microglia eliminated for thereafter. We have revealed that microglia are essential for plaque development and in their absence plaques are not formed and instead A? accumulates within the vasculature. Notably, this phenotype resembles that of AD mice containing human ApoE ? the strongest risk factor for AD. This finding places microglia as initiators of the disease and suggests that plaques form because of microglia, and that this is not due to a reduction in microglia-mediated A? clearance. This proposal will fully characterize how pathology develops in the absence of microglia, in multiple mouse models, and determine the mechanisms by which microglia trap A? within the parenchyma and lead to plaque formation. We hypothesize that microglia take up neuronally derived A?, in an ApoE-dependent fashion, and then concentrate it within lysosomal compartments. This buildup leads to microglial cell death, releasing the A?, which then seeds a plaque. Thus, we will explore how microglial cause plaques, and what the role of ApoE is in this process.